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Clinical Trial Results:
A Three Arm Double blind, Randomised Multicentre Study to Investigate the Non-Inferiority of a Soft Gel Capsule of Ibuprofen Lipid Formulation (total daily dose 1200 mg) versus a Standard Soft Gel Ibuprofen Capsule (total daily dose 1200 mg and 2400 mg) in the Treatment of Patients with Episodic Knee Arthralgia/Flaring Knee Pain.

Summary
EudraCT number	2014-004254-33
Trial protocol	NL GB
Global end of trial date	10 Aug 2016

Results information
Results version number	v2(current)
This version publication date	25 May 2022
First version publication date	18 Apr 2022
Other versions	v1
Version creation reason	Correction of full data set Non-serious adverse event occurrence data updated.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

IFH-2014-002

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Infirst+ HEALTHCARE Ltd

Sponsor organisation address

45 Beech Street, London, United Kingdom, EC2Y 8AD

Public contact

Director of Regulatory Affairs, Infirst+ HEALTHCARE Ltd, medinfo@infirst.co.uk

Scientific contact

Director of Regulatory Affairs, Infirst+ HEALTHCARE Ltd, medinfo@infirst.co.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

21 Mar 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Aug 2016

Global end of trial reached?

Yes

Global end of trial date

10 Aug 2016

Was the trial ended prematurely?

Main objective of the trial

To determine if a 5 day treatment course of 1200 mg/day of ibuprofen in lipid formulation is non inferior to standard ibuprofen capsules (either 1200 mg /day or 2400 mg/day) for the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in patients suffering from episodic knee arthralgia/knee flare pain.

Protection of trial subjects

The study was conducted in accordance with the principles of Good Clinical Practice (GCP), the Declaration of Helsinki and applicable European clinical trials directives and local regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Mar 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 135

Country: Number of subjects enrolled

United Kingdom: 329

Worldwide total number of subjects

464

EEA total number of subjects

135

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

370

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was conducted at 20 centres in the UK and 7 centres in The Netherlands. Recruitment was stopped early after 464 patients had been randomised into the study, of which 462 patients received study drug. Randomisation ranged between 107 patients (of which 106 patients were treated) at one centre to 1 patient each at others.

Screening details

For patients identified by the Healthcare Professional, the Healthcare Professional eliminated any patient who did not meet the study inclusion/exclusion criteria, which specifically excluded patients with other risk factors for gastric bleeding, in particular in the 60-70 years age group.

Period 1 title

Course 1 (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

This was a double-blind study. The IMP, comparator product, and placebo were blinded. They were identical in size and shape and their appearance was that of soft, white gelatin capsules.

Are arms mutually exclusive

Yes

Lipid 1200 group

Arm description

5-day treatment course of 200 mg soft gel capsule of ibuprofen lipid formulation.

Arm type

Experimental

Investigational medicinal product name

Ibuprofen

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

5-day treatment course of 200 mg soft gel capsule of ibuprofen lipid formulation (2 capsules to be taken 3 times a day, 6 hours apart [morning, afternoon, and evening]).

Soft Gel 1200 group

Arm description

5-day treatment course of one 400 mg soft gel capsule ibuprofen plus placebo capsule.

Arm type

Active comparator

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

5-day treatment course of one 400 mg soft gel capsule ibuprofen plus placebo capsule (1 of each - total 2 capsules - to be taken 3 times a day, 6 hours apart [morning, afternoon, and evening]).

Investigational medicinal product name

Ibuprofen

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

5-day treatment course of one 400 mg soft gel capsule ibuprofen plus placebo capsule (1 of each - total 2 capsules - to be taken 3 times a day, 6 hours apart [morning, afternoon, and evening]).

Soft Gel 2400 group

Arm description

5-day treatment course of 400 mg soft gel capsule ibuprofen.

Arm type

Active comparator

Investigational medicinal product name

Ibuprofen

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

5-day treatment course of 400 mg soft gel capsule ibuprofen (2 capsules to be taken 3 times a day, 6 hours apart [morning, afternoon, and evening]).

Number of subjects in period 1	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Started	150	155	159
Completed	142	149	150
Not completed	8	6	9
Adverse event, non-fatal	2	2	5
Other	2	-	-
Lost to follow-up	2	-	-
most frequent- patients attended the clinic early	-	4	4
Protocol deviation	2	-	-

Baseline characteristics

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Reporting group title

Lipid 1200 group

Reporting group description

5-day treatment course of 200 mg soft gel capsule of ibuprofen lipid formulation.

Reporting group title

Soft Gel 1200 group

Reporting group description

5-day treatment course of one 400 mg soft gel capsule ibuprofen plus placebo capsule.

Reporting group title

Soft Gel 2400 group

Reporting group description

5-day treatment course of 400 mg soft gel capsule ibuprofen.

Reporting group values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group	Total
Number of subjects	150	155	159	464
Age categorical
Units: Subjects
<65 years	114	130	124	368
≥65 years	34	25	35	94
Not recorded	2	0	0	2
Gender categorical
Units: Subjects
Female	61	64	65	190
Male	87	91	94	272
Not recorded	2	0	0	2
Ethnicity
Units: Subjects
Asian	5	5	3	13
Black	6	5	2	13
White	131	142	152	425
Other	6	3	2	11
Not recorded	2	0	0	2
Index knee
Units: Subjects
Left	75	84	88	247
Right	73	71	71	215
Not recorded	2	0	0	2
Number of patients with at least 1 medical history
Units: Subjects
Number of patients with at least 1 medical history	141	147	148	436
Number of patients with no medical history	7	8	11	26
Not recorded	2	0	0	2
Surgical and medical procedures
Surgical and medical procedures (N/group): - Appendicectomy: 4 / 5 / 4 - Meniscus removal: 4 / 4 / 3 - Hysterectomy: 4 / 3 / 3 Medical History Reported for >2% of Patients. Subjects can appear in more than preferred term.
Units: Subjects
Surgical and medical procedures	35	36	40	111
No surgical and medical procedures	113	119	119	351
Not recorded	2	0	0	2
Gastrointestinal disorders
Gastrointestinal disorders (N/group): - Dyspepsia: 10 / 13 / 14 - Gastrooesophageal reflux disease: 6 / 5 / 11 - Irritable bowel syndrome: 4 / 6 / 4 Medical History Reported for >2% of Patients. Subjects can appear in more than preferred term.
Units: Subjects
Gastrointestinal disorders	31	37	38	106
No gastrointestinal disorders	117	118	121	356
Not recorded	2	0	0	2
Vascular disorders
Vascular disorders (N/group): - Hypertension: 28 / 30 / 26 - Essential hypertension: 4 / 5 / 4 Medical History Reported for >2% of Patients. Subjects can appear in more than preferred term.
Units: Subjects
Vascular disorders	35	38	33	106
No vascular disorders	113	117	126	356
Not recorded	2	0	0	2
Metabolism and nutrition disorders
Metabolism and nutrition disorders (N/group)*: - Type 2 diabetes mellitus: 11 / 17 / 14 - Hypercholesterolaemia: 9 / 16 / 12
Units: Subjects
Metabolism and nutrition disorders	21	37	29	87
No metabolism and nutrition disorders	127	118	130	375
Not recorded	2	0	0	2
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders (N/group): - Asthma: 10 / 12 / 12 Medical History Reported for >2% of Patients.
Units: Subjects
Respiratory, thoracic and mediastinal disorders	20	18	19	57
No respiratory, thoracic and mediastinal disorders	128	137	140	405
Not recorded	2	0	0	2
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders (N/group): - Eczema: 3 / 5 / 3 Medical History Reported for >2% of Patients.
Units: Subjects
Skin and subcutaneous tissue disorders	25	20	10	55
No skin and subcutaneous tissue disorders	123	135	149	407
Not recorded	2	0	0	2
Investigations
Investigations (N/group): - Arthroscopy: 11 / 9 / 7 - Blood cholesterol increased: 7 / 3 / 6 Medical History Reported for >2% of Patients. Subjects can appear in more than preferred term.
Units: Subjects
Investigations	19	16	18	53
No Investigations	129	139	141	409
Not recorded	2	0	0	2
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications (N/group): - Meniscus injury: 4 / 4 / 3 Medical History Reported for >2% of Patients.
Units: Subjects
Injury, poisoning and procedural complications	20	18	14	52
No injury, poisoning and procedural complications	128	137	145	410
Not recorded	2	0	0	2
Infections and infestations
Units: Subjects
Infections and infestations	16	15	15	46
No infections and infestations	132	140	144	416
Not recorded	2	0	0	2
Psychiatric disorders
Psychiatric disorders (N/group): - Depression: 11 / 6 / 10 Medical History Reported for >2% of Patients.
Units: Subjects
Psychiatric disorders	18	9	13	40
No psychiatric disorders	130	146	146	422
Not recorded	2	0	0	2
Nervous system disorders
Units: Subjects
Nervous system disorders	14	10	13	37
No nervous system disorders	134	145	146	425
Not recorded	2	0	0	2
Reproductive system and breast disorders
Reproductive system and breast disorders (N/group): - Erectile dysfunction: 3 / 4 / 5 Medical History Reported for >2% of Patients.
Units: Subjects
Reproductive system and breast disorders	7	15	13	35
No reproductive system and breast disorders	141	140	146	427
Not recorded	2	0	0	2
Immune system disorders
Immune system disorders (N/group): - Seasonal allergy: 4 / 2 / 8 Medical History Reported for >2% of Patients.
Units: Subjects
Immune system disorders	5	3	14	22
No immune system disorders	143	152	145	440
Not recorded	2	0	0	2
Endocrine disorders
Endocrine disorders (N/group): - Hypothyroidism: 7 / 6 / 4 Medical History Reported for >2% of Patients.
Units: Subjects
Endocrine disorders	9	6	6	21
No endocrine disorders	139	149	153	441
Not recorded	2	0	0	2
Eye disorders
Units: Subjects
Eye disorders	9	7	4	20
No eye disorders	139	148	155	442
Not recorded	2	0	0	2
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
Units: Subjects
Neoplasms benign, malignant and unspecified	7	4	9	20
No neoplasms benign, malignant and unspecified	141	151	150	442
Not recorded	2	0	0	2
Cardiac disorders
Units: Subjects
Cardiac disorders	8	5	6	19
No cardiac disorders	140	150	153	443
Not recorded	2	0	0	2
Ear and labyrinth disorders
Units: Subjects
Ear and labyrinth disorders	5	6	8	19
No ear and labyrinth disorders	143	149	151	443
Not recorded	2	0	0	2
General disorders and administration site conditions
Units: Subjects
General disorders and admin. site conditiions	3	2	6	11
No general disorders and admin. site conditiions	145	153	153	451
Not recorded	2	0	0	2
Renal and urinary disorders
Units: Subjects
Renal and urinary disorders	1	4	6	11
No renal and urinary disorders	147	151	153	451
Not recorded	2	0	0	2
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders (N/group): - Osteoarthritis: 59 / 63 / 65 - Arthralgia: 38 / 40 / 44 - Back pain: 9 / 7 / 12 Medical History Reported for >2% of Patients. Subjects can appear in more than preferred term.
Units: Subjects
Musculoskeletal and connective tissue disorders	98	112	114	324
No musculoskeletal and connective tissue disorders	50	43	45	138
Not recorded	2	0	0	2
WOMAC total score
WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index WOMAC scores range from 0 (best outcome) to 10 (worst outcome). Number of patients analysed per group was 144, 152 and 154, respectively.
Units: Score
arithmetic mean (standard deviation)	5.44 ( 1.74 )	5.49 ( 1.62 )	5.45 ( 1.70 )	-
WOMAC stiffness score
WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index WOMAC scores range from 0 (best outcome) to 10 (worst outcome). Number of patients analysed per group was 144, 152 and 154, respectively.
Units: Score
arithmetic mean (standard deviation)	6.38 ( 1.91 )	6.06 ( 1.96 )	6.15 ( 2.03 )	-
WOMAC function score
WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index WOMAC scores range from 0 (best outcome) to 10 (worst outcome). Number of patients analysed per group was 144, 152 and 154, respectively.
Units: Score
arithmetic mean (standard deviation)	5.25 ( 1.92 )	5.39 ( 1.71 )	5.32 ( 1.82 )	-
WOMAC pain scale score
WOMAC scores range from 0 (best outcome) to 10 (worst outcome). Number of patients analysed per group was 145, 152 and 155, respectively.
Units: Score
arithmetic mean (standard deviation)	5.72 ( 1.64 )	5.60 ( 1.69 )	5.61 ( 1.64 )	-
GSRS total score
GSRS: Gastrointestinal Symptom Rating Scale Number of patients analysed per group was 145, 149 and 154, respectively.
Units: Score
arithmetic mean (standard deviation)	1.30 ( 0.53 )	1.36 ( 0.55 )	1.34 ( 0.47 )	-
GSRS Dimension Score - Abdominal pain score
GSRS: Gastrointestinal Symptom Rating Scale Number of patients analysed per group was 145, 151 and 155, respectively.
Units: Score
arithmetic mean (standard deviation)	1.28 ( 0.58 )	1.26 ( 0.52 )	1.26 ( 0.52 )	-
GSRS Dimension Score - Constipation score
GSRS: Gastrointestinal Symptom Rating Scale Number of patients analysed per group was 145, 151 and 155, respectively.
Units: Score
arithmetic mean (standard deviation)	1.26 ( 0.63 )	1.36 ( 0.78 )	1.26 ( 0.56 )	-
GSRS Dimension Score - Diarrhoea score
GSRS: Gastrointestinal Symptom Rating Scale Number of patients analysed per group was 145, 151 and 154, respectively.
Units: Score
arithmetic mean (standard deviation)	1.21 ( 0.69 )	1.30 ( 0.64 )	1.31 ( 0.66 )	-
GSRS Dimension Score - Indigestion score
GSRS: Gastrointestinal Symptom Rating Scale Number of patients analysed per group was 145, 150 and 155, respectively.
Units: Score
arithmetic mean (standard deviation)	1.44 ( 0.76 )	1.53 ( 0.80 )	1.48 ( 0.69 )	-
GSRS Dimension Score - Reflux score
GSRS: Gastrointestinal Symptom Rating Scale Number of patients analysed per group was 145, 150 and 155, respectively.
Units: Score
arithmetic mean (standard deviation)	1.21 ( 0.72 )	1.25 ( 0.76 )	1.32 ( 0.63 )	-
NRS score - Pain
NRS: Numerical Rating Score Pain scores range from 0 (best outcome) to 10 (worst outcome). Number of patients analysed per group was 145, 152 and 155, respectively.
Units: Score
arithmetic mean (standard deviation)	7.0 ( 1.1 )	6.8 ( 1.2 )	6.7 ( 1.2 )	-
NRS score - Stiffness
NRS: Numerical Rating Score Stiffness scores range from 0 (best outcome) to 10 (worst outcome). Number of patients analysed per group was 145, 152 and 155, respectively.
Units: Score
arithmetic mean (standard deviation)	6.6 ( 2.0 )	6.1 ( 2.3 )	6.2 ( 2.2 )	-
NRS score - Patient-nominated activity performance
NRS: Numerical Rating Score Patient-nominated activity performance scores range from 0 (best outcome) to 10 (worst outcome). Number of patients analysed per group was 145, 152 and 155, respectively.
Units: Score
arithmetic mean (standard deviation)	6.9 ( 1.8 )	6.8 ( 1.6 )	6.8 ( 1.8 )	-
NRS score - Swelling
NRS: Numerical Rating Score Swelling scores range from 0 (best outcome) to 10 (worst outcome). Number of patients analysed per group was 145, 152 and 155, respectively.
Units: Score
arithmetic mean (standard deviation)	3.9 ( 3.0 )	3.6 ( 2.7 )	3.9 ( 2.9 )	-
Global Assessment NRS
NRS: Numerical Rating Score Global assessment scores range from 0 (very well) to 10 (very poorly). Number of patients analysed per group was 145, 149 and 155, respectively.
Units: Score
arithmetic mean (standard deviation)	6.5 ( 1.6 )	6.5 ( 1.7 )	6.4 ( 1.7 )	-

End points

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Reporting group title

Lipid 1200 group

Reporting group description

5-day treatment course of 200 mg soft gel capsule of ibuprofen lipid formulation.

Reporting group title

Soft Gel 1200 group

Reporting group description

5-day treatment course of one 400 mg soft gel capsule ibuprofen plus placebo capsule.

Reporting group title

Soft Gel 2400 group

Reporting group description

5-day treatment course of 400 mg soft gel capsule ibuprofen.

Primary: Change from baseline after 5 days of treatment in the WOMAC pain scale score

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End point title

Change from baseline after 5 days of treatment in the WOMAC pain scale score

End point description

WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index

End point type

Primary

End point timeframe

Day 5

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	145	152	155
Units: Change from baseline
least squares mean (confidence interval 95%)	-2.42 (-2.76 to -2.09)	-2.16 (-2.49 to -1.84)	-2.61 (-2.94 to -2.29)

Lipid 1200 vs Soft Gel 1200

Comparison groups

Soft Gel 1200 group v Lipid 1200 group

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.2327

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.69

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.22

Notes
[1] - n in analysis = 297 (Lipid 1200=145, soft gel 1200=152)

Lipid 1200 vs Soft Gel 2400

Comparison groups

Lipid 1200 group v Soft Gel 2400 group

Number of subjects included in analysis

300

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.3799

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

0.62

Variability estimate

Standard error of the mean

Dispersion value

0.22

Notes
[2] - n in analysis = 300 (Lipid 1200=145, soft gel 2400=155)

Secondary: Change from baseline after 5 days of treatment in the GSRS total score

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End point title

Change from baseline after 5 days of treatment in the GSRS total score

End point description

GSRS: Gastrointestinal Symptom Rating Scale

End point type

Secondary

End point timeframe

Day 5

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	145	152 ^[3]	155 ^[4]
Units: Change from baseline
least squares mean (confidence interval 95%)	0.08 (-0.00 to 0.16)	0.05 (-0.03 to 0.14)	0.13 (0.05 to 0.21)

Notes
[3] - 149 included in analysis
[4] - 154 included in analysis

No statistical analyses for this end point

Secondary: Change from baseline after 5 days of treatment in the WOMAC total, stiffness, and function scale scores

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End point title

Change from baseline after 5 days of treatment in the WOMAC total, stiffness, and function scale scores

End point description

WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index

End point type

Secondary

End point timeframe

Day 5

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	145 ^[5]	152 ^[6]	155 ^[7]
Units: Change from baseline
least squares mean (confidence interval 95%)
Total score	-2.32 (-2.63 to -2.01)	-2.18 (-2.49 to -1.87)	-2.53 (-2.84 to -2.23)
Stiffness score	-2.78 (-3.16 to -2.40)	-2.38 (-2.75 to -2.02)	-2.80 (-3.17 to -2.43)
Function score	-2.26 (-2.57 to -1.95)	-2.14 (-2.44 to -1.83)	-2.46 (-2.77 to -2.16)

Notes
[5] - Number of patients in analysis: Total score =144, Stiffness score =144, Function score =145
[6] - Number of patients in analysis: Total score=149, Stiffness score=152, Function score=149
[7] - Number of patients in analysis: Total score=154, Stiffness score=154, Function score=155

No statistical analyses for this end point

Secondary: Change from baseline after 5 days of treatment in the GSRS dimension scores

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End point title

Change from baseline after 5 days of treatment in the GSRS dimension scores

End point description

Change from baseline after 5 days of treatment in the GSRS dimension scores of diarrhoea, indigestion, constipation, abdominal pain and reflux syndromes. GSRS: Gastrointestinal Symptom Rating Scale

End point type

Secondary

End point timeframe

Day 5

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	145	152 ^[8]	155 ^[9]
Units: Change from baseline
least squares mean (confidence interval 95%)
Abdominal pain score	0.11 (0.00 to 0.22)	0.14 (0.04 to 0.25)	0.18 (0.08 to 0.29)
Constipation score	0.11 (0.00 to 0.22)	0.06 (-0.05 to 0.17)	0.06 (-0.04 to 0.17)
Diarrhoea score	0.08 (-0.04 to 0.19)	0.01 (-0.11 to 0.12)	0.12 (0.01 to 0.23)
Indigestion score	0.03 (-0.09 to 0.15)	0.02 (-0.09 to 0.14)	0.12 (0.00 to 0.23)
Reflux score	0.07 (-0.08 to 0.21)	0.08 (-0.06 to 0.23)	0.21 (0.07 to 0.36)

Notes
[8] - n in analysis: Abdominal=151, Constipation=151, Diarrhoea=151, Indigestion=150, Reflux=150
[9] - n in analysis: Abdominal=155, Constipation=155, Diarrhoea=154, Indigestion=155, Reflux=155

No statistical analyses for this end point

Secondary: Change from baseline after each day of study treatment in the NRS scores of pain, stiffness, patient-nominated activity performance and swelling

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End point title

Change from baseline after each day of study treatment in the NRS scores of pain, stiffness, patient-nominated activity performance and swelling

End point description

Change from baseline after each day of study treatment in the NRS scores of pain, stiffness, patient-nominated activity performance and swelling.

End point type

Secondary

End point timeframe

Day 6

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	145	152	155
Units: Change from baseline
least squares mean (confidence interval 95%)
Pain	-3.4 (-3.8 to -3.0)	-3.1 (-3.4 to -2.7)	-3.6 (-3.9 to -3.2)
Stiffness	-3.2 (-3.6 to -2.8)	-3.0 (-3.4 to -2.6)	-3.4 (-3.8 to -3.1)
Patient-Nominated Activity	-3.3 (-3.7 to -2.9)	-3.0 (-3.4 to -2.6)	-3.5 (-3.9 to -3.1)
Swelling	-1.7 (-2.0 to -1.3)	-1.2 (-1.5 to -0.9)	-1.7 (-2.0 to -1.4)

No statistical analyses for this end point

Secondary: Change from baseline in Global Assessment NRS after 5 days of treatment

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End point title

Change from baseline in Global Assessment NRS after 5 days of treatment

End point description

NRS: Numerical Rating Score

End point type

Secondary

End point timeframe

Day 5

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	145	152 ^[10]	155
Units: Change from baseline
least squares mean (confidence interval 95%)	-2.8 (-3.2 to -2.4)	-2.6 (-3.0 to -2.3)	-3.1 (-3.5 to -2.7)

Notes
[10] - 149 included in analysis

No statistical analyses for this end point

Secondary: OMERACT-OARSI response after 5 days of treatment

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End point title

OMERACT-OARSI response after 5 days of treatment

End point description

OMERACT: Outcome Measures in Rheumatology OARSI: Osteoarthritis Research Society International Response defined as improvement in WOMAC pain or function of ≥ 50% with change of ≥ 2, or improvement in at least 2 of: 1) pain ≥ 20% with change of ≥ 1, 2) function ≥ 20% with change of ≥ 1, 3) global assessment ≥ 20% with change of ≥ 1.

End point type

Secondary

End point timeframe

Day 5

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	145	152	155
Units: Percentage of responders
number (confidence interval 95%)	73.1 (65.1 to 80.1)	69.7 (61.8 to 76.9)	76.1 (68.6 to 82.6)

No statistical analyses for this end point

Secondary: Knee flare category

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End point title

Knee flare category

End point description

Percentage of responders after 5 days of treatment. Knee Flare Response Categories were: 'Fully controlled' , 'Under control' , 'Partially controlled' , 'Not under control'. Response defined as knee flare category of 'Fully controlled' or 'Under control'.

End point type

Secondary

End point timeframe

Day 5

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	145	152	155
Units: Percentage of responders
number (confidence interval 95%)	55.9 (47.4 to 64.1)	49.3 (41.1 to 57.6)	59.4 (51.2 to 67.2)

No statistical analyses for this end point

Secondary: Resolution of knee flare

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End point title

Resolution of knee flare

End point description

Resolution of knee flare was a calculated term defined as the first occurrence of 2 consecutive days with pain NRS score <4, or knee flare under control at end of the course and pain NRS score <4

End point type

Secondary

End point timeframe

Day 5

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	145	152	155
Units: Percentage of patients with resolution
number (not applicable)	44.8	41.4	53.5

No statistical analyses for this end point

Secondary: Summary of Adverse Events

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End point title

Summary of Adverse Events

End point description

End point type

Secondary

End point timeframe

Day 5

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	148	155	159
Units: Subjects
number (not applicable)
Patients with at least 1 AE	54	53	65
Worst severity of AE - Mild	38	33	45
Worst severity of AE - Moderate	14	18	18
Worst severity of AE - Severe	2	2	2
Patients with at least 1 drug-related AE	28	37	50
Patients with at least 1 AE leading to discont.	2	2	5
Patients with at least 1 SAE	0	0	1

No statistical analyses for this end point

Secondary: Vital Signs at Baseline and End of Treatment

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End point title

Vital Signs at Baseline and End of Treatment

End point description

SBP = Systolic blood pressure DBP = Diastolic blood pressure BMI = Body mass index

End point type

Secondary

End point timeframe

Day 5

End point values	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Number of subjects analysed	148	155	159
Units: Specified for each category
arithmetic mean (standard deviation)
SBP-baseline (mmHg)	133.6 ( 15.4 )	132.1 ( 15.3 )	134.3 ( 16.3 )
SBP-change from baseline (mmHg)	-0.7 ( 12.2 )	1.6 ( 11.1 )	1.3 ( 11.6 )
DBP-baseline (mmHg)	78.5 ( 9.8 )	77.9 ( 10.5 )	78.9 ( 9.7 )
DBP-change from baseline (mmHg)	0.4 ( 7.0 )	0.4 ( 8.3 )	1.0 ( 8.1 )
Pulse Rate-baseline (bpm)	71.2 ( 10.2 )	70.1 ( 10.3 )	72.4 ( 10.0 )
Pulse Rate-change from baseline (bpm)	-0.2 ( 8.2 )	-0.8 ( 8.6 )	-1.5 ( 8.4 )
BMI-baseline (kg/sq.metre)	28.39 ( 4.68 )	28.66 ( 4.53 )	28.60 ( 4.54 )
BMI-change from baseline (kg/sq.metre))	0.13 ( 0.33 )	0.09 ( 0.51 )	0.06 ( 0.31 )
Temperature-baseline (degrees C)	36.52 ( 0.37 )	36.44 ( 0.40 )	36.51 ( 0.39 )
Temperature-change from baseline (degrees C)	-0.09 ( 0.41 )	-0.02 ( 0.39 )	-0.06 ( 0.40 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The Investigator instructed the patient to report any new AE that occurred within 30 days of completing their last study treatment, for possible assessment and follow-up.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Lipid 1200 group

Reporting group description

Reporting group title

Soft Gel 1200 group

Reporting group description

Reporting group title

Soft Gel 2400 group

Reporting group description

Serious adverse events	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 148 (0.00%)	0 / 155 (0.00%)	1 / 159 (0.63%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Reproductive system and breast disorders
Endometriosis
subjects affected / exposed	0 / 148 (0.00%)	0 / 155 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	Lipid 1200 group	Soft Gel 1200 group	Soft Gel 2400 group
Total subjects affected by non serious adverse events
subjects affected / exposed	54 / 148 (36.49%)	53 / 155 (34.19%)	65 / 159 (40.88%)
Investigations
Investigations
subjects affected / exposed	0 / 148 (0.00%)	1 / 155 (0.65%)	2 / 159 (1.26%)
occurrences all number	0	1	2
Blood pressure increased
subjects affected / exposed	0 / 148 (0.00%)	1 / 155 (0.65%)	2 / 159 (1.26%)
occurrences all number	0	1	2
Vascular disorders
Vascular disorders
subjects affected / exposed	2 / 148 (1.35%)	1 / 155 (0.65%)	1 / 159 (0.63%)
occurrences all number	2	1	1
Hypertension
subjects affected / exposed	2 / 148 (1.35%)	1 / 155 (0.65%)	1 / 159 (0.63%)
occurrences all number	2	1	1
Nervous system disorders
Nervous system disorders
subjects affected / exposed	5 / 148 (3.38%)	4 / 155 (2.58%)	3 / 159 (1.89%)
occurrences all number	5	5	3
Headache
subjects affected / exposed	2 / 148 (1.35%)	3 / 155 (1.94%)	1 / 159 (0.63%)
occurrences all number	2	3	1
Dizziness
subjects affected / exposed	2 / 148 (1.35%)	0 / 155 (0.00%)	2 / 159 (1.26%)
occurrences all number	2	0	2
General disorders and administration site conditions
General disorders and administration site conditions
subjects affected / exposed	6 / 148 (4.05%)	3 / 155 (1.94%)	5 / 159 (3.14%)
occurrences all number	6	3	5
Fatigue
subjects affected / exposed	2 / 148 (1.35%)	0 / 155 (0.00%)	2 / 159 (1.26%)
occurrences all number	2	0	2
Gastrointestinal disorders
Gastrointestinal disorders
subjects affected / exposed	39 / 148 (26.35%)	47 / 155 (30.32%)	53 / 159 (33.33%)
occurrences all number	83	99	129
Diarrhoea
subjects affected / exposed	10 / 148 (6.76%)	12 / 155 (7.74%)	9 / 159 (5.66%)
occurrences all number	12	15	13
Nausea
subjects affected / exposed	10 / 148 (6.76%)	8 / 155 (5.16%)	9 / 159 (5.66%)
occurrences all number	10	9	9
Abdominal discomfort
subjects affected / exposed	8 / 148 (5.41%)	5 / 155 (3.23%)	12 / 159 (7.55%)
occurrences all number	8	5	14
Abdominal distension
subjects affected / exposed	6 / 148 (4.05%)	5 / 155 (3.23%)	15 / 159 (9.43%)
occurrences all number	6	5	15
Dyspepsia
subjects affected / exposed	5 / 148 (3.38%)	8 / 155 (5.16%)	12 / 159 (7.55%)
occurrences all number	5	8	14
Constipation
subjects affected / exposed	8 / 148 (5.41%)	7 / 155 (4.52%)	9 / 159 (5.66%)
occurrences all number	9	7	9
Flatulence
subjects affected / exposed	5 / 148 (3.38%)	8 / 155 (5.16%)	6 / 159 (3.77%)
occurrences all number	5	8	6
Abdominal pain upper
subjects affected / exposed	4 / 148 (2.70%)	8 / 155 (5.16%)	6 / 159 (3.77%)
occurrences all number	5	8	6
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 148 (0.68%)	6 / 155 (3.87%)	8 / 159 (5.03%)
occurrences all number	1	6	8
Eructation
subjects affected / exposed	4 / 148 (2.70%)	4 / 155 (2.58%)	6 / 159 (3.77%)
occurrences all number	4	4	6
Gastrointestinal motility disorder
subjects affected / exposed	2 / 148 (1.35%)	6 / 155 (3.87%)	5 / 159 (3.14%)
occurrences all number	2	6	5
Abdominal pain
subjects affected / exposed	3 / 148 (2.03%)	3 / 155 (1.94%)	6 / 159 (3.77%)
occurrences all number	4	3	6
Gastrointestinal sounds abnormal
subjects affected / exposed	3 / 148 (2.03%)	5 / 155 (3.23%)	4 / 159 (2.52%)
occurrences all number	3	5	4
Defaecation urgency
subjects affected / exposed	3 / 148 (2.03%)	2 / 155 (1.29%)	5 / 159 (3.14%)
occurrences all number	3	2	5
Abdominal pain lower
subjects affected / exposed	0 / 148 (0.00%)	0 / 155 (0.00%)	2 / 159 (1.26%)
occurrences all number	0	0	2
Faeces hard
subjects affected / exposed	1 / 148 (0.68%)	4 / 155 (2.58%)	3 / 159 (1.89%)
occurrences all number	1	4	3
Abdominal tenderness
subjects affected / exposed	1 / 148 (0.68%)	0 / 155 (0.00%)	2 / 159 (1.26%)
occurrences all number	1	0	2
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders
subjects affected / exposed	1 / 148 (0.68%)	1 / 155 (0.65%)	2 / 159 (1.26%)
occurrences all number	2	2	2
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders
subjects affected / exposed	1 / 148 (0.68%)	2 / 155 (1.29%)	1 / 159 (0.63%)
occurrences all number	1	2	1
Infections and infestations
Infections and infestations
subjects affected / exposed	4 / 148 (2.70%)	1 / 155 (0.65%)	4 / 159 (2.52%)
occurrences all number	4	1	4
Gastroenteritis
subjects affected / exposed	2 / 148 (1.35%)	0 / 155 (0.00%)	1 / 159 (0.63%)
occurrences all number	2	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

08 Oct 2015

The qualifying number of knee flare pain episodes in the previous 12 months was reduced from 2 to 1 (note this change was not expected to alter the study population because the severity of the current knee flare was still assessed in the same way, i.e. an NRS score of 5 or above at baseline).

08 Oct 2015

The method of identifying prospective study patients was changed from using a keyword search of the GP database to approach by a HCP. Patients were then referred to the study centre for informed consent and enrolment. The relationship between the patient’s GP and the investigative site was clarified.

08 Oct 2015

The required duration of contraceptive use for female patients of childbearing potential was reduced from 90 days to 30 days.

08 Oct 2015

The exclusion criteria concerning concomitant use of medications for chronic pain was revised to clarify the difference between pain medications that were taken regularly (and so were excluded if they had been taken within 4 weeks prior to baseline visit) and pain medication that was taken on an intermittent basis (which were permitted as long as a dose has not been taken within 7 days prior to the baseline visit).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline after 5 days of treatment in the WOMAC pain scale score

Primary: Change from baseline after 5 days of treatment in the WOMAC pain scale score

Secondary: Change from baseline after 5 days of treatment in the GSRS total score

Secondary: Change from baseline after 5 days of treatment in the GSRS total score

Secondary: Change from baseline after 5 days of treatment in the WOMAC total, stiffness, and function scale scores

Secondary: Change from baseline after 5 days of treatment in the WOMAC total, stiffness, and function scale scores

Secondary: Change from baseline after 5 days of treatment in the GSRS dimension scores

Secondary: Change from baseline after 5 days of treatment in the GSRS dimension scores

Secondary: Change from baseline after each day of study treatment in the NRS scores of pain, stiffness, patient-nominated activity performance and swelling

Secondary: Change from baseline after each day of study treatment in the NRS scores of pain, stiffness, patient-nominated activity performance and swelling

Secondary: Change from baseline in Global Assessment NRS after 5 days of treatment

Secondary: Change from baseline in Global Assessment NRS after 5 days of treatment

Secondary: OMERACT-OARSI response after 5 days of treatment

Secondary: OMERACT-OARSI response after 5 days of treatment

Secondary: Knee flare category

Secondary: Knee flare category

Secondary: Resolution of knee flare

Secondary: Resolution of knee flare

Secondary: Summary of Adverse Events

Secondary: Summary of Adverse Events

Secondary: Vital Signs at Baseline and End of Treatment

Secondary: Vital Signs at Baseline and End of Treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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